Merja  Laine  3.12.2015

DIABETEKSEN  KÄYPÄ  HOITO    -­‐SUOSITUKSEN  

PÄIVITYS  12.9.2013  

Diabetic retinopathy Leading cause of blindness in working-age adults1

Diabetic nephropathy Leading cause of end-stage renal disease2

Cardiovascular disease

Stroke 2- to 4-fold increase in cardiovascular

mortality and stroke3

Diabetic neuropathy Leading cause of non-traumatic lower extremity amputations5

   Tyypin  2  diabetes  ja  komplikaaHot  

Diabeettinen retinopatia

Suurin sokeuteen johtava syy työikäisillä aikuisilla1

Diabeettinen nefropatia

Suurin syy loppuvaiheen munuaissairauteen2

Aivohalvaus Aivohalvaus ja SVT -kuolleisuus lisääntyvät 2-4 -kertaisesti3

Sydän –ja verisuonitauti

8/10 diabeetikosta kuolee SVT -tapahtumien seurauksena4

Diabeettinen neuropatia

Suurin syy ei-traumaattisiin raaja-amputaatioihin5

1.  Fong  et  al.  Diabetes  Care  2003;  2.  Molitch  et  al.  Diabetes  Care  2003;  3.  Kannel  et  al.  Am  Heart  J  1990;  4.  Hogan  et  al  Diabetes  care  2003;  5.  Mayfield  et  al.  diabetes  Care  2003  

Diabetes  Käypä  Hoito  suositus  2013  

Diabetes  Käypä  Hoito  suositus  2013  

-­‐   glukoosi  -­‐   lipidit  -­‐   verenpaine  -­‐   ASAn  mielekäs  käyMö    -­‐   painon  hallinta    -­‐   ruokavalio    -­‐   liikunta  -­‐   tupakoinO  -­‐   alkoholin  käyMö  

Tyypin  2  diabeteksen  patofysiologia  

more stringent

less stringent

Patient attitude and expected treatment efforts highly motivated, adherent,

excellent self-care capacities less motivated, non-adherent,

poor self-care capacities

Risks potentially associated with hypoglycemia and other drug adverse effects

low high

Disease duration newly diagnosed long-standing

Life expectancy long short

Important comorbidities absent severe few / mild

Established vascular complications absent severe few / mild

Readily available limited

Usually not modifiable

Potentially modifiable

HbA1c&7%&&

PATIENT / DISEASE FEATURES

Approach to the management of hyperglycemia

Resources and support system

Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

Diabetes  käypä  hoito  2013  

ADA/EASD  2015  

Diabetes KH 2013

Hoidon  seuranta  

CV  death  is  increased  in  paHents  with  diabetes  and  mulHple  risk  factors  

Risk  factors  were  serum  cholesterol  ≥200  mg/dL,  current  smoker,  SBP  ≥120  mmHg    Stamler  et  al.  Diabetes  Care  1993;16:434.  

0  

20  

40  

60  

80  

100  

120  

140  

0   1   2   3  Age-­‐adjusted

 CVD

 death  risk/10,000  

person

-­‐years  

Number  of  risk  factors  

Diabetes  No  diabetes  

34.7  %  tyypin  2  diabeeHkoista  on                    merkiWävä  munuaisvaurio        

(eGFR  <  60  ml/min  ja/tai  albuminuria)  

Metsärinne  K,  Bröijersen  A,  Kantola  I,  Niskanen  L,  Rissanen  A,  Appelroth  T  ,  Pöntynen  N  ,    Poussa  T,  Koivisto  V  ,  Virkamäki  A.    Primary  Care  Diabetes  2014.  

Diabetes  Care  2011;34:1431-­‐37  

•  kreaCl  45-­‐60  ml/min:  meaormiinia  voi  jatkaa,  munuaistoiminnan  kontrolli  3-­‐6kk  välein  

 •  kreaCl  30-­‐45  ml/min:  erityinen  varovaisuus,  50%  

pienenneMy  annos  tai  puolet  maksimista,  ei  uuMa  aloitusta,  tarkka  monitoroinO  

 •  kreaCl  <30  ml/min:  meaormiinin  lopetus    •  tauotus  akuuOn  sairauden  yhteydessä,  erityistä  tarkkuuMa  

monisairailla  ja  polyfarmasiassa  

Meaormiini  ja  munuaisten  vajaatoiminta  

•  Chronic metformin use results in vitamin B12 deficiency in 30% of patients.

•  Vitamin B12 deficiency, which may present without anemia and as a peripheral neuropathy, is often misdiagnosed as diabetic neuropathy

•  Failure to diagnose the cause of the neuropathy will result in progression of central and/or peripheral neuronal damage which can be arrested but not reversed with vitamin B12 replacement.

Diabetes käypä hoito 2013

sic! 4/2013, Jorma Lahtela

HOITOSUUNNITELMA  

•  HoitotavoiMeiden  pohOminen  poOlaan  kanssa  yhdessä  

 •  Kontrollit          -­‐  mitä          -­‐  milloin          -­‐  kenellä  

Diabetes  käypä  hoito  2013  

Diabetes  is  associated  with  significant                loss  of  life  years  

     Seshasai  et  al.  N  Engl  J  Med  2011;364:829-­‐41.  

0

7

6

5

4

3

2

1

0 40 50 60 70 80 90

Age (year)

Year

s of

life

lost

Men 7

6

5

4

3

2

1

0 40 50 60 70 80 90 0

Age (year)

Women Non-vascular deaths Vascular deaths

On average, a 50-year old with diabetes but no history of vascular disease is ~6 years younger at time of death than a counterpart without diabetes

Study1 Baseline HbA1c Control vs intensive

Mean duration of diabetes at

baseline (years) Microvascular CVD Mortality

UKPDS 9%→ 7.9% vs 7% Newly diagnosed ↓ ↔ ↔

ACCORD1–3 8.3%→ 7.5% vs 6.4% 10.0   ↓* ↔ ↑

ADVANCE 7.5 %→ 7.3% vs 6.5% 8.0   ↓ ↔ ↔

VADT 9.4 %→ 8.4% vs 6.9% 11.5   ↓ ↔ ↔

Glucose-­‐lowering  studies  confirmed  benefit  on  microvascular  complicaHons  but  mixed  results  on  macrovascular  outcomes  

*No  change  in  primary  microvascular  composite  but  significant  decreases  in  micro/macroalbuminuria2,3  **No  change  in  major  clinical  microvascular  events  but  significant  reducOon  in  ESRD                (p  =  0.007)5  

 1.  Table  adapted  from  Bergenstal  et  al.  Am  J  Med  2010;123:374.e9–e18.    2.  Genuth  et  al.  Clin  Endocrinol    Metab  2012;97:41–8.    3.  Ismail-­‐Beigi  et  al.  Lancet  2010;376:419–30.    4.  Hayward  et  al.  N  Engl  J  Med  2015;372:2197-­‐206  (VADT).    5.  Zoungas  et  al.  N  Engl  J  Med  2014;371:1392-­‐406.  

Long-­‐term  follow-­‐up1,4,5    

↓ ↓ ↔ ↓ ↔ ↓

↓ ↔** ↔ ↔ ↔ ↔

↓ ? ↔ ↓ ↔ ↔

Urinary glucose excretion via SGLT2 inhibition1

1. Bakris et al. Kidney Int 2009;75;1272–7.

SGLT2 SGLT2

inhibitor

SGLT1

SGLT2 inhibitors reduce glucose

reabsorption in the proximal

tubule, leading to urinary glucose excretion* and

osmotic diuresis

Filtered glucose load > 180 g/day

EMPA-REG OUTCOME®: Study design

Zinman et al. Cardiovasc Diabetol 2014;13:102.

Placebo run-in

2 weeks

Empagliflozin 10 mg QD + usual care

Empagliflozin 25 mg QD + usual care

Placebo + usual care

Screening (n = 11,507)

Background therapy adjustment allowed after Week 12

12 weeks of stable background glucose-lowering therapy

Visit 1

Week 4 8 12 16 28 40 52 0 -2 -3

Visit 3 Visits 4–7 every 4 weeks

Visits 8–10 every 12 weeks

Visits every 14 weeks

Visit 2

Follo

w-u

p

R

End of study visit

+30 days

Aim Compound-specific To determine CV safety of empagliflozin vs placebo + usual care for glycaemic control and CV risk in patients with T2D and high CV risk

CV death

26

Empagliflozin 10 mg HR 0.65

(95% CI 0.50, 0.85) p=0.0016

Empagliflozin 25 mg HR 0.59

(95% CI 0.45, 0.77) p=0.0001

Cumulative incidence function. HR, hazard ratio

Hospitalisation for heart failure

27

Empagliflozin 10 mg HR 0.62

(95% CI 0.45, 0.86) p=0.0044

Empagliflozin 25 mg HR 0.68

(95% CI 0.50, 0.93) p=0.0166

Cumulative incidence function. HR, hazard ratio

All-cause mortality

28

HR 0.68 (95% CI 0.57, 0.82)

p<0.0001

Empagliflozin 10 mg HR 0.70

(95% CI 0.56, 0.87) p=0.0013

Empagliflozin 25 mg HR 0.67

(95% CI 0.54, 0.83) p=0.0003

Kaplan-Meier estimate. HR, hazard ratio

Empagliflozin modulates several factors related to CV risk

Adapted from Inzucchi SE,Zinman, B, Wanner, C et al. Diab Vasc Dis Res 2015;12:90-100

!BP !Arterial stiffness

!Glucose !Insulin

!Albuminuria

!Uric acid

Other

↑LDL-C ↑HDL-C

!Triglycerides

!Oxidative stress

!Sympathetic nervous system

activity

!Weight !Visceral adiposity